Nucleotides such as ATP (adenosine triphosphate) and ADP (adenosine diphosphate) are chemical transmitters present in all mammalian tissues. These molecules are released from cells, and then bind to two kinds of P2 receptor families (purinergic receptors), that is, the G protein-coupled type P2Y receptor subfamily and the ion transport type P2X receptor subfamily, present in the cellular membrane of other cells, to thereby cause various important physiological actions and pathological actions. Examples of these physiological actions include pain in central nerves, blood coagulation caused by platelet-derived ATP, and the like (Non-Patent Documents 1 and 2). In order to induce the physiological actions caused by these ATP and/or ADP, ATP or ADP needs to be released (or secreted) from cells. Therefore, a medicament regulating the transport of ATP and/or ADP is thought to be useful as a medicament for treating or preventing pain in central nerves, or as a medicament capable of regulating blood coagulation caused by platelet-derived ATP.
However, although it is known that there exist a number of mechanisms for the release of ATP or ADP (Non-Patent Documents 1 and 2), many issues still remain unclear in regard to the mechanisms and the molecules involved in the mechanisms.
One of the mechanisms involves the release of ATP from endothelial cells, epithelial cells, hepatic cells or the like, due to stresses such as tension or hypotonic treatment. A second mechanism involves continual ATP secretion from osteoblasts or epithelial cells. A third mechanism is based on the regulatory exocytosis observed in nerve cells or neuroendocrine cells, glial cells or the like (FIG. 1). Exocytosis of ATP is the most important process from pharmacological and physiological aspects, but its molecular mechanism is not well known. In order for the exocytosis of ATP to occur, ATP first needs to be accumulated in the secretory vesicles. In fact, it is known that ATP is concentrated in the synaptic vesicles or dense-cored vesicles of nerves, the synaptic vesicle-like organelles (synaptic-like microvesicles) of glial cells, and the like. The process for the concentration of ATP is unclear, but it is thought that a certain active transporter is involved in the process.
The only transporter in mammals that has been confirmed so far to have ATP transport ability is the ATP/ADP exchanger (Non-Patent Documents 1 and 2). This transporter is a transporter that is present in the inner membrane of mitochondria, and exchanges the ADP present in the cytoplasm with the ATP synthesized in the mitochondria. In regard to transporters other than this, it has been recently reported that Mcd4 membrane protein and Sad p membrane protein are in charge of ATP transport in the Golgi body and the endoplasmic reticulum (Non-Patent Documents 3 to 5). Mcd4 is a kind of ATPAse, while Sad p is a transporter of the same type as the ATP/ADP exchanger. However, none of these transporters are proteins that directly participate in the exocytosis of ATP. The nature of the transporters, which transport ATP in various secretory vesicles, is still not known. Once these ATP transporters are elucidated, it will then be possible to understand the mechanism of chemical transmission involving ATP at a molecular level, and it will be also possible to artificially control the physiological phenomena and pathological phenomena in which the chemical transmission involving ATP takes part. For example, when the nature of these transporters is understood, it will be possible to search and develop a specific inhibitor by employing its transporter. Such an inhibitor is expected to be useful as a medicament for controlling pain or platelet coagulation.
Bibliographical information on the technologies of the related art, to which the invention of this application is pertained, is as follows.
[Non-Patent Document 1] Burnstock G. (2006) TIPS 27, 166-176.
[Non-Patent Document 2] Lazarowski E (2006) Purinergic signaling in neuron-glia interactions. Wiley. Chibester (Novartis Foundation Symposium 276), p. 73-90.
[Non-Patent Document 3] Mayinger P, Bankaitis V A, Meyer D I. (1995) J. Cell Biol. 131, 1377-1386.
[Non-Patent Document 4] Puglielli L, Mandon E C, Hirschberg C B. (1999) J. Biol. Chem. 274, 12665-12669.
[Non-Patent Document 5] Coco S et al. (2003) J. Biol. Chem. 278, 1354-1362.